Preterm Epo Neuroprotection Trial (PENUT Trial) CCC

描述(由申请人提供)：在美国，每年约有30,600名婴儿在怀孕28周(40周为足月)之前出生。这些被称为极低胎龄新生儿(ELGAN)的婴儿具有很高的发病率和死亡率：入住NICU的极低胎龄新生儿中有20%在出院前死亡，20%的幸存者有重度和20%的中度神经发育障碍(NDI)。这些婴儿的围产期护理费用每年超过180亿美元，约占新生儿护理医院总费用的一半。需要新的方法来改善这些结果。重组促红细胞生成素(EPO)是一种很有前途的新型神经保护剂。它广泛可用，价格实惠，并已安全地用于新生儿刺激红细胞生成。有大量的临床前数据支持其 用作神经保护干预：EPO通过减少炎症、氧化和导致细胞凋亡的兴奋性毒性损伤来减少缺氧缺血后的急性脑损伤；EPO还通过增加神经发生、血管生成和保护少突胶质细胞促进正常脑成熟。我们假设新生儿促红细胞生成素治疗将在月经后24-26个月将死亡或重度NDI的综合结果从40%降至30%(主要结果)，或将中度NDI从60%降至40%(次要结果)。我们的具体目标是比较376名接受EPO治疗的婴儿和376名对照组婴儿，以确定：1)EPO是否减少了24-26个月PMA(NDI定义为存在：CP或Bayley III婴幼儿认知或运动发育量表的存在)的综合结局；2)新生儿大剂量EPO治疗对老年人的短期、中期和长期安全性；3)新生儿EPO治疗是否降低循环炎症介质和脑损伤生物标志物的一系列指标；4)治疗36周时，MRI测量EPO治疗是否改善脑结构(灰质体积、白质体积、小脑体积、脑回和基于脑束的空间统计)。在一个探索性的目标中，我们将确定哪种MRI定量指标最能预测PMA 24-26个月的神经发育。我们预计，与安慰剂相比，EPO治疗Elgans将在PMA的24-26个月时改善神经发育结果，并将为这一组脆弱的婴儿提供急需的治疗。此外，我们预计EPO治疗将是安全的，将减少脑损伤和炎症的生物标记物，并将与36周PMA时MRI所确定的较少的早产儿脑损伤相关。协调中心将与联系的发展协调委员会密切合作，以实现拟议的目标。中心将为所有地点提供临床领导和支持，而疾病预防控制中心将为研究的监测和最终报告提供数据收集、管理、质量控制、操作支持和数据分析方面的系统和监督。

DESCRIPTION (provided by applicant): In the U.S., approximately 30,600 infants per year are born before 28 weeks of gestation (40 weeks is term). These infants, termed Extremely Low Gestational Age Neonates (ELGANs), experience high morbidity and mortality: 20% of ELGANs admitted to an NICU die before discharge, 20% of survivors have severe and 20% moderate neurodevelopmental impairment (NDI). Perinatal care costs for these infants exceed $18 billion every year and account for approximately half of total hospital charges for newborn care. New approaches are needed to improve these outcomes. Recombinant erythropoietin (Epo) is a promising novel neuroprotective agent. It is widely available, affordable, and has been used safely in neonates to stimulate erythropoiesis. There are extensive preclinical data to support its use as a neuroprotective intervention: Epo decreases acute brain injury following hypoxia ischemia by decreasing inflammation, oxidative and excitotoxic injury which results in decreased apoptosis; Epo also promotes normal brain maturation by increasing neurogenesis, angiogenesis, and by protecting oligodendrocytes. We hypothesize that neonatal Epo treatment of ELGANs will decrease the combined outcome of death or severe NDI from 40% to 30% (primary outcome), or moderate NDI from 60% to 40% (secondary outcome) measured at 24-26 months post menstrual age (PMA). Our specific aims are to compare 376 Epo-treated with 376 control infants to determine: 1) whether Epo decreases the combined outcome of death or NDI at 24-26 months PMA (NDI is defined as the presence of: CP or Bayley III Scales of Infant and Toddler Development cognitive or motor scale < 70); 2) the short-, intermediate- and long-term safety of neonatal high dose Epo administration to ELGANs; 3) whether neonatal Epo treatment decreases serial measures of circulating inflammatory mediators, and biomarkers of brain injury; 4) whether Epo treatment improves brain structure (volume of gray matter, white matter and cerebellum, brain gyrification, and tract-based spatial statistics) at 36 weeks PMA as measured by MRI. In an exploratory aim, we will determine which MRI quantitative measures best predict neurodevelopment at 24-26 months PMA. We anticipate that Epo treatment of ELGANs will confer improved neurodevelopmental outcome at 24-26 months PMA compared to placebo, and will provide a much-needed therapy for this group of vulnerable infants. Furthermore, we anticipate that Epo treatment will be safe, will decrease biomarkers of brain injury and inflammation, and will be associated with less preterm brain injury as determined by MRI at 36 weeks PMA. The CCC will work closely with the linked DCC to accomplish the proposed goals. The CCC will provide the clinical leadership and support for all sites, and the DCC will provide the systems and oversight for data collection, management, quality control, operational support and data analyses for the monitoring and final reporting of the study.